Results of the ADJUVANT trial established adjuvant gefitinib as an optimal choice for EGFR-mutated stage II-IIIA NSCLC patients. However, clinical benefit varied among patients. To investigate this heterogeneity, we performed comprehensive tumor genomic analyses on these patients. Here, we report the predictive MEDUSA model (Multiple-biomarker Evaluation to Determine the Utilization of Specific Adjuvant therapy) that can guide clinical decision of adjuvant therapy.
171 baseline specimens from ADJUVANT (n = 95, gefitinib arm; n = 76, vinorelbine plus cisplatin [VP] arm) underwent targeted sequencing (Geneseeq 422-gene panel). Predictive biomarkers were identified by Cox regression with gene-by-treatment interactions, and a multi-gene composite score was developed to compare the benefits of these treatments.
EGFR mutations were confirmed in all cases. TP53, NKX2-1, CDK4, MYC and RB1 were identified as predictive biomarkers. Specifically, gefitinib-favoring biomarkers include TP53 exon4/5 mutations (interaction HR [iHR] 0.33, 95% CI 0.12-0.93, p = 0.035), and copy number gain of NKX2-1 (iHR 0.26, 95% CI 0.098-0.68, p = 0.006), CDK4 (iHR 0.14, 95% CI 0.025-0.77, p = 0.024) and MYC (iHR 0.10, 95% CI 0.011-0.98, p = 0.048). RB1 alterations strongly favored VP (iHR 4.07, 95% CI 1.56-10.53, p = 0.004). The MEDUSA model was developed based on the above, and stratified patients into 3 groups: Strong Gefitinib-favoring (SG, n = 60), Moderate Gefitinib-favoring (MG, n = 87), and VP-favoring (VP, n = 24). Notably, the SG group demonstrated significant OS benefit with adjuvant gefitinib as well: HR of OS was 0.44 (95% CI 0.2-0.98, p = 0.04).Table: 1441PD
|MEDUSA Score||mDFS (m)||2y DFS(%)||HR(95% CI)||P|
|SG||≤-0.5||34.5 vs 9.1||70.3 vs 11.0||0.21 (0.1-0.43)||<0.0001|
|MG||-0.5 to 0.5||32.8 vs 20.7||67.5 vs 41.0||0.61 (0.35-1.07)||0.08|
|VP||≥0.5||19.3 vs 34.2||41.6 vs 69.2||3.07 (0.98-9.52)||0.04|
Incorporating alterations in TP53, NKX2-1, CDK4, MYC and RB1, MEDUSA score could guide personalized adjuvant therapy for resected stage II-IIIA EGFR-mutant NSCLC patients.
Clinical trial identification
NCT01405079; Release at July 29. 2011.
Legal entity responsible for the study
Chinese Thoracic Oncology Group (CTONG).
Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. H. Bao: Full / Part-time employment: Geneseeq Technology Inc. Toronto. Y. Chen: Full / Part-time employment: Geneseeq Technology Inc. Nanjing. Y.W. Shao: Full / Part-time employment: Geneseeq Technology Inc. Nanjing. All other authors have declared no conflicts of interest.